Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer's disease.

Synapse number is the best indicator of cognitive impairment In Alzheimer's disease (AD), yet the respective contributions of Aβ and tau, particularly human wild-type tau, to synapse loss remain undefined. Here, we sought to elucidate the Aβ-dependent changes in wild-type human tau that trigger synapse loss and cognitive decline in AD by generating two novel transgenic mouse models. The first overexpresses floxed human APP with Swedish and London mutations under the thy1 promoter, and recapitulates important features of early AD, including accumulation of soluble Aβ and oligomers, but no plaque formation. Transgene excision via Cre-recombinase reverses cognitive decline, even at 18-months of age. Secondly, we generated a human wild-type tau-overexpressing mouse. Crossing of the two animals accelerates cognitive impairment, causes enhanced accumulation and aggregation of tau, and results in reduction of dendritic spines compared to single transgenic hTau or hAPP mice. These results suggest that Aβ-dependent acceleration of wild-type human tau pathology is a critical component of the lasting changes to dendritic spines and cognitive impairment found in AD.